Endogenous estrogens are largely responsible for the development and maintenance of the
female reproductive system and secondary sexual characteristics. Although circulating estrogens
exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its metabolites, estrone and
estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which
secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.
After menopause, most endogenous estrogen is produced by conversion of androstenedione,
secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate
conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.
To date, two estrogen receptors have been identified. These vary in proportion from
tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing
hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism.
Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Pharmacokinetics
A. Absorption
Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the
gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.
In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal ring)
rapidly increased serum estradiol (E2) levels. The time to attain peak serum estradiol levels
(Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly
over the next 24 hours and were virtually indistinguishable from the baseline mean
(range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks
during which the ring was maintained in the vaginal vault remained relatively unchanged
(see Table 1).
The initial estradiol peak post-application of the second ring in the same women resulted in
~38 percent lower Cmax, apparently due to reduced systemic absorption
via the treated vaginal epithelium. The relative systemic exposure from the initial peak of
ESTRING accounted for approximately 4 percent of the total estradiol exposure over the
12-week period.
The release of estradiol from ESTRING was demonstrated in a Phase II study of 222 postmenopausal
women who inserted up to four rings consecutively at three-month intervals. Systemic delivery of
estradiol from ESTRING resulted in mean steady state serum estradiol estimates of
7.8, 7.0, 7.0, 8.1 pg/mL at weeks 12, 24, 36, and 48, respectively.
Similar reproducibility is also seen in levels of estrone. The systemic exposure to estradiol and
estrone was within the range observed in untreated women after the first eight hours.
In postmenopausal women, mean dose of estradiol systemically absorbed unchanged from ESTRING
is ~8 percent [95 percent CI: 2.8–12.8 percent] of the daily amount released locally.
TABLE 1: PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE ESTRING APPLICATION
B. Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens.
Estrogens are widely distributed in the body and are generally found in higher concentrations
in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone
binding globulin (SHBG) and albumin.
C. Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens.
Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.
These transformations take place mainly in the liver. Estradiol is converted reversibly to
estrone, and both can be converted to estriol, which is the major urinary metabolite.
Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation
in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the
intestine followed by reabsorption. In postmenopausal women, a significant proportion of the
circulating estrogens exist as sulfate conjugates, especially estrone sulfate,
which serves as a circulating reservoir for the formation of more active estrogens.
D. Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and
sulfate conjugates.
Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application of
ESTRING in a Phase I study was 5 percent and 8 percent, respectively, of the daily released amount.
E. Special Populations
ESTRING has not been studied in patients with hepatic or renal impairment.
F. Drug Interactions
No formal drug interactions studies have been done with ESTRING.
In vitro and in vivo studies have shown that systemic estrogens are metabolized partially by
cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen
metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum),
phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens,
possibly resulting in a decrease in systemic effects and/or changes in the uterine bleeding profile.
Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and
grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.